The overall goal of this Program is to advance understanding of the role played by cellular oxidative events in cancer biology and therapy. The influence of peroxidative events and experimental oxidative modulations on the biology of established tumors and the perturbations induced by treatment continue to be the focus of all projects. State-of-the-art techniques in antioxidant enzyme transfection, lipid membrane modification and analysis, radical detection by electron paramagnetic resonance (EPR), molecular biology of transcription factors and quantitation of cellular lipid peroxidation by multiple complementary approaches will be used. Four projects, each directed by established investigators in two departments, provide an integrated approach to the objectives. All projects have made progress during the 48 months of funding, including identification of superoxide dismutase as a cancer suppressor enzyme/gene, identification of a new mechanism for cancer drug resistance based on oxidation, demonstration that small molecule antioxidants protect membranes from oxidative stress of anticancer drugs, emphasis on bis-allylic positions as determinant of membranes and lipid oxidative susceptibility, and demonstration that apoptosis in HL60 cells requires a peroxidase. The proposed funding period will be characterized by emphasis on in vivo transfection studies, the role of nitric oxide in cancer therapy, a new estimation of cellular oxidative state, transcription factors, and the mechanism of apoptosis. The overall structure of the Program is similar to the last submission, The interaction of the projects is extensive. The Cores will continue to provide state-of-the-art expertise. In summary, this Program will take advantage of the natural interactions of the investigators in four related projects, each utilizing two scientific cores, to solve the important and underinvestigated role of oxidation and lipids in cancer therapeutics.